基于生物信息学的慢性阻塞性肺疾病频繁和非频繁加重患者潜在微小RNA生物标志物的鉴定
Bioinformatics-based identification of potential microRNA biomarkers in frequent and non-frequent exacerbators of COPD.
作者信息
Liu Xiao, Qu Jingge, Xue Weixiao, He Liangai, Wang Jun, Xi Xuejiao, Liu Xiaoxia, Yin Yunhong, Qu Yiqing
机构信息
Department of Respiratory Medicine, Qilu Hospital of Shandong University, Jinan, People's Republic of China.
Department of Rheumatology, Second Hospital of Harbin Medical University, Harbin, People's Republic of China.
出版信息
Int J Chron Obstruct Pulmon Dis. 2018 Apr 16;13:1217-1228. doi: 10.2147/COPD.S163459. eCollection 2018.
OBJECTIVES
MicroRNAs (miRNAs) play essential roles in the development of COPD. In this study, we aimed to identify and validate potential miRNA biomarkers in frequent and non-frequent exacerbators of COPD patients using bioinformatic analysis.
MATERIALS AND METHODS
The candidate miRNA biomarkers in COPD were screened from Gene Expression Omnibus (GEO) dataset and identified using GEO2R online tool. Then, we performed bioinformatic analyses including target prediction, gene ontology (GO), pathway enrichment analysis and construction of protein-protein interaction (PPI) network. Furthermore, the expression of the identified miRNAs in peripheral blood monocular cells (PBMCs) of COPD patients was validated using quantitative real-time polymerase chain reaction (qRT-PCR).
RESULTS
MiR-23a, miR-25, miR-145 and miR-224 were identified to be significantly downregulated in COPD patients compared with healthy controls. GO analysis showed the four miRNAs involved in apoptotic, cell differentiation, cell proliferation and innate immune response. Pathway analysis showed that the targets of these miRNAs were associated with p53, TGF-β, Wnt, VEGF and MAPK signal pathway. In healthy controls, the miR-25 and miR-224 levels were significantly decreased in smokers compared with nonsmokers (<0.001 and <0.05, respectively). In COPD patients, the levels of miR-23a, miR-25, miR-145 and miR-224 were associated with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages. Notably, miR-23a and miR-145 were significantly elevated in non-frequent exacerbators compared with frequent exacerbators (<0.05), and miR-23a showed higher area under the receiver-operator characteristic curve (AUROC) than miR-145 (0.707 vs 0.665, <0.05).
CONCLUSION
MiR-23a, miR-25, miR-145 and miR-224 were associated with the development of COPD, and miR-23a might be a potential biomarker for discriminating the frequent exacerbators from non-frequent exacerbators.
目的
微小RNA（miRNA）在慢性阻塞性肺疾病（COPD）的发展中起重要作用。在本研究中，我们旨在通过生物信息学分析，鉴定并验证COPD患者频繁和非频繁急性加重期潜在的miRNA生物标志物。
材料与方法
从基因表达综合数据库（GEO）数据集中筛选COPD的候选miRNA生物标志物，并使用在线工具GEO2R进行鉴定。然后，我们进行了生物信息学分析，包括靶标预测、基因本体论（GO）、通路富集分析以及蛋白质-蛋白质相互作用（PPI）网络构建。此外，使用定量实时聚合酶链反应（qRT-PCR）验证所鉴定的miRNA在COPD患者外周血单核细胞（PBMC）中的表达。
结果
与健康对照相比，miR-23a、miR-25、miR-145和miR-224在COPD患者中显著下调。GO分析显示这四种miRNA参与凋亡、细胞分化、细胞增殖和固有免疫反应。通路分析表明这些miRNA的靶标与p53、转化生长因子-β（TGF-β）、Wnt、血管内皮生长因子（VEGF）和丝裂原活化蛋白激酶（MAPK）信号通路相关。在健康对照中，吸烟者的miR-25和miR-224水平与非吸烟者相比显著降低（分别<0.001和<0.05）。在COPD患者中，miR-23a、miR-25、miR-145和miR-224的水平与慢性阻塞性肺疾病全球倡议（GOLD）分期相关。值得注意的是，与频繁急性加重期患者相比，非频繁急性加重期患者的miR-23a和miR-145显著升高（<0.05），并且miR-23a的受试者工作特征曲线下面积（AUROC）高于miR-145（0.707对0.665，<0.05）。
结论
miR-23a、miR-25、miR-145和miR-224与COPD的发展相关，并且miR-23a可能是区分频繁急性加重期和非频繁急性加重期的潜在生物标志物。
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